The microsomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride (TG), cholesteryl ester (CE), and phosphatidylcholine (PC) between small unilamellar vesicles (SUV). Wetterau & Zilversmit, Chem. Phys. Lipids 38, 205-22 (1985). When transfer rates are expressed as the percent of the donor lipid transferred per time, MTP expresses a distinct preference for neutral lipid transport (TG and CE), relative to phospholipid transport. The protein from bovine liver has been isolated and characterized. Wetterau & Zilversmit, Chem. Phys. Lipids 38, 205-22 (1985). Polyacrylamide gel electrophoresis (PAGE) analysis of the purified protein suggests that the transfer protein is a complex of two subunits of apparent molecular weights 58,000 and 88,000, since a single band was present when purified NTP was electrophoresed under nondenaturing condition, while two bands of apparent molecular weights 58,000 and 88,000 were identified when electrophoresis was performed in the presence of sodium dodecyl sulfate (SDS). These two polypeptides are hereinafter referred to as 58 kDa and 88 kDa, respectively, or the 58 kDa and the 88 kDa component of MTP, respectively, or the low molecular weight subunit and the high molecular weight subunit of MTP, respectively.
Characterization of the 58,000 molecular weight component of bovine MTP indicates that it is the previously characterized multifunctional protein, protein disulfide isomerase (PDI). Wetterau et al., J. Biol. Chem. 265, 9800-7 (1990). The presence of PDI in the transfer protein is supported by evidence showing that (1) the amino terminal 25 amino acids of the bovine 58,000 kDa component of MTP is identical to that of bovine PDI, and (2) disulfide isomerase activity was expressed by bovine MTP following the dissociation of the 58 kDa-88 kDa protein complex. In addition, antibodies raised against bovine PDI, a protein which by itself has no TG transfer activity, were able to immunoprecipitate bovine TG transfer activity from a solution containing purified bovine MTP.
PDI normally plays a role in the folding and assembly of newly synthesized disulfide bonded proteins within the lumen of the endoplasmic reticulum. Bulleid & Freedman, Nature 335, 649-51 (1988). It catalyzes the proper pairing of cysteine residues into disulfide bonds, thus catalyzing the proper folding of disulfide bonded proteins. In addition, PDI has been reported to be identical to the beta subunit of human prolyl 4-hydroxylase. Koivu et al., J. Biol. Chem. 262, 6447-9 (1987). The role of PDI in the bovine transfer protein is not clear. It does appear to be an essential component of the transfer protein as dissociation of PDI from the 88 kDa component of bovine MTP by either low concentrations of a denaturant (guanidine HCl), a chaotropic agent (sodium perchlorate), or a nondenaturing detergent (octyl glucoside) results in a loss of transfer activity. Wetterau et al., Biochemistry 30, 9728-35 (1991). Isolated bovine PDI has no apparent lipid transfer activity, suggesting that either the 88 kDa polypeptide is the transfer protein or that it confers transfer activity to the protein complex.
The tissue and subcellular distribution of MTP activity in rats has been investigated. Wetterau & Zilversmit, Biochem. Biophys. Acta 875, 610-7 (1986). Lipid transfer activity was found in liver and intestine. Little or no transfer activity was found in plasma, brain, heart, or kidney. Within the liver, MTP was a soluble protein located within the lumen of the microsomal fraction. Approximately equal concentrations were found in the smooth and rough microsomes.
Abetalipoproteinemia is an autosomal recessive disease characterized by a virtual absence of plasma lipoproteins which contain apolipoprotein B (apoB). Kane & Havel in The Metabolic Basis of Inherited Disease, Sixth edition, 1139-64 (1989). Plasma TG levels may be as low as a few mg/dL, and they fail to rise after fat ingestion. Plasma cholesterol levels are often only 20-45 mg/dL.
These abnormalities are the result of a genetic defect in the assembly and/or secretion of very low density lipoproteins (VLDL) in the liver and chylomicrons in the intestine. The molecular basis for this defect has not been previously determined. In subjects examined, triglyceride, phospholipid, and cholesterol synthesis appear normal. At autopsy, subjects are free of atherosclerosis. Schaefer et al., Clin. Chem. 34, B9-12 (1988). A link between the apoB gene and abetalipoproteinemia has been excluded in several families. Talmud et al., J. Clin. Invest. 82, 1803-6 (1988) and Huang et al., Am. J. Hum. Genet. 46, 1141-8 (1990).
Subjects with abetalipoproteinemia are afflicted with numerous maladies. Kane & Havel, supra. Subjects have fat malabsorption and TG accumulation in their enterocytes and hepatocytes. Due to the absence of TG-rich plasma lipoproteins, there is a defect in the transport of fat-soluble vitamins such as vitamin E. This results in acanthocytosis of erythrocytes, spinocerebellar ataxia with degeneration of the fasciculus cuneatus and gracilis, peripheral neuropathy, degenerative pigmentary retinopathy, and ceroid myopathy. Treatment of abetalipoproteinemic subjects includes dietary restriction of fat intake and dietary supplementation with vitamins A, E and K.
In vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. Wetterau & Zilversmit, Biochem. Biophys. Acta 875, 610-7 (1986). The ability of MTP to catalyze the transport of TG between membranes is consistent with this hypothesis, and suggests that MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER.
Olofsson and colleagues have studied lipoprotein assembly in HepG2 cells. Bostrom et al., J. Biol. Chem. 263, 4434-42 (1988). Their results suggest small precursor lipoproteins become larger with time. This would be consistent with the addition or transfer of lipid molecules to nascent lipoproteins as they are assembled. MTP may play a role in this process. In support of this hypothesis, Howell and Palade, J. Cell Biol. 92, 833-45 (1982), isolated nascent lipoproteins from the hepatic Golgi fraction of rat liver. There was a spectrum of sizes of particles present with varying lipid and protein compositions. Particles of high density lipoprotein (HDL) density, yet containing apoB, were found. Higgins and Hutson, J. Lipid Res. 25, 1295-1305 (1984), reported lipoproteins isolated from Golgi were consistently larger than those from the endoplasmic reticulum, again suggesting the assembly of lipoproteins is a progressive event. However, there is no direct evidence in the prior art demonstrating that MTP plays a role in lipid metabolism or the assembly of plasma lipoprotein.
Recent reports (Science, Vol. 258, page 999, 1992; D. Sharp et al, Nature, Vol. 365, page 65, 1993) demonstrate that the defect causing abetalipoproteinemia is in the MTP gene, and as a result, the NTP protein. Individuals with abetalipoproteinemia have no MTP activity, as a result of mutations in the MTP gene, some of which have been characterized. These results indicate that MTP is required for the synthesis of apoB containing lipoproteins, such as VLDL, the precursor to LDL. It therefore follows that inhibitors of MTP would inhibit the synthesis of VLDL and LDL, thereby lowering VLDL levels, LDL levels, cholesterol levels, and triglyceride levels in animals and man.
Canadian Patent Application No. 2,091,102 published Mar. 2, 1994 (corresponding to U.S. application Ser. No. 117,362, filed Sep. 3, 1993 (file DC21b)) which is incorporated herein by reference), reports MTP inhibitors which also block the production of apoB containing lipoproteins in a human hepatic cell line (HepG2 cells). This provides further support for the proposal that an MTP inhibitor would lower apoB containing lipoprotein and lipid levels in vivo. This Canadian patent application discloses a method for identifying the MTP inhibitors ##STR6##
which has the name 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-3-oxo-1H-isoindole hydrochloride and ##STR7##
which has the name 1-[3-(6-fluoro-1-tetralanyl)-methyl]-4-O-methoxyphenyl piperazine.
EP 0643057A1 published Mar. 15, 1995, discloses MTP inhibitors of the structure ##STR8##
where X is ##STR9## PA1 R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; ##STR10## PA1 where m is 2 or 3; PA1 R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl (wherein alkyl has at least 2 carbons), diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl (wherein alkyl has at least 2 carbons), cycloalkyl, or cycloalkylalkyl (wherein alkyl has at least 2 carbons); all of the aforementioned R.sup.1 groups being optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; or PA1 R.sup.1 is a group of the structure ##STR11## PA1 R.sup.11 is a bond, alkylene, alkenylene or alkynylene of up to 6 carbon atoms, arylene (for example ##STR12## PA1 or mixed arylene-alkylene (for example ##STR13## PA1 where n is 1 to 6; PA1 R.sup.12 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, haloalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy, heteroarylalkyl or cycloalkylalkyl; PA1 Z is a bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene of from 1 to 5 carbon atoms; PA1 R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, carboxy, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; PA1 or R.sup.1 is ##STR14## PA1 wherein p is 1 to 8 and R.sup.17 and R.sup.18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl, at least one of R.sup.17 and R.sup.18 being other than H; PA1 or R.sup.1 is ##STR15## PA1 wherein R.sup.19 is aryl or heteroaryl; PA1 R.sup.20 is aryl or heteroaryl; PA1 R.sup.21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy; PA1 R.sup.2, R.sup.3, R.sup.4 are independently hydrogen, halo, alkyl, haloalkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; PA1 R.sup.5 is alkyl of at least 2 carbons, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, all of the R.sup.5 and R.sup.6 substituents being optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino (wherein the amino includes 1 or 2 substituents which are alkyl, or aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino; with the proviso that when R.sup.5 is CH.sub.3, R.sup.6 is not H; and where R.sup.5 is phenyl, the phenyl preferably includes an ortho hydrophobic substituent such as alkyl, haloalkyl, aryl, aryloxy or arylalkyl; PA1 R.sup.6 is hydrogen or C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkenyl; PA1 R.sup.7 is alkyl, aryl or arylalkyl wherein alkyl or the alkyl portion is optionally substituted with oxo; and PA1 including pharmaceutically acceptable salts and anions thereof. PA1 where Q is ##STR17## PA1 X is: CHR.sup.8, ##STR18## PA1 R.sup.8, R.sup.9 and R.sup.10 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; PA1 Y is --(CH.sub.2).sub.m -- or ##STR19## PA1 wherein m is 2 or 3; PA1 R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl wherein alkyl has at least 2 carbons, diarylalkyl, arylalkenyl, diarylalkenyl, arylalkynyl, diarylalkynyl, diarylalkylaryl, heteroarylalkyl wherein alkyl has at least 2 carbons, cycloalkyl, or cycloalkylalkyl wherein alkyl has at least 2 carbons, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from halo, haloalkyl, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, fluorenyl, heteroarylalkyl, hydroxy or oxo; PA1 or R.sup.1 is a fluorenyl-type group of the structure ##STR20## PA1 R.sup.1 is an indenyl-type group of the structure ##STR21## PA1 Z.sup.1 and Z.sup.2 are the same or different and are independently a bond, O, S, ##STR22## PA1 with the proviso that with respect to B, at least one of Z.sup.1 and Z.sup.2 will be other than a bond; R.sup.11 is a bond, alkylene, alkenylene or alkynylene of up to 10 carbon atoms; arylene or mixed arylene-alkylene; R.sup.12 is hydrogen, alkyl, alkenyl, aryl, haloalkyl, trihaloalkyl, trihaloalkylalkyl, heteroaryl, heteroarylalkyl, arylalkyl, arylalkenyl, cycloalkyl, aryloxy, alkoxy, arylalkoxy or cycloalkylalkyl, with the provisos that PA1 Z is bond, O, S, N-alkyl, N-aryl, or alkylene or alkenylene from 1 to 5 carbon atoms; R.sup.13, R.sup.14, R.sup.15, and R.sup.16 are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, hydroxy, alkoxy, nitro, amino, thio, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl or aryloxy; PA1 R.sup.15a and R.sup.16a are independently hydrogen, alkyl, halo, haloalkyl, aryl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylthio, arylthio, aminocarbonyl, alkylcarbonyloxy, arylcarbonylamino, alkylcarbonylamino, arylalkyl, heteroaryl, heteroarylalkyl, or aryloxy; PA1 or R.sup.1 is a group of the structure ##STR24## PA1 wherein p is 1 to 8 and R.sup.17 and R.sup.18 are each independently H, alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl at least one of R.sup.17 and R.sup.18 being other than H; PA1 or R.sup.1 is a group of the structure ##STR25## PA1 wherein R.sup.19 is aryl or heteroaryl; PA1 R.sup.20 is aryl or heteroaryl; PA1 R.sup.21 is H, alkyl, aryl, alkylaryl, arylalkyl, aryloxy, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, cycloalkyl, cycloalkylalkyl or cycloalkylalkoxy; PA1 R.sup.2, R.sup.3, R.sup.4 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; PA1 R.sup.5 is independently alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, arylalkoxy, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, heteroarylcarbonyl, amino, alkylamino, arylamino, heteroarylamino, cycloalkyloxy, cycloalkylamino, all. optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl; PA1 R.sup.6 is hydrogen or C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkenyl; all optionally substituted with 1, 2, 3 or 4 groups which may independently be any of the substituents listed in the definition of R.sup.5 set out above; PA1 R.sup.7 is alkyl, aryl or arylalkyl wherein alkyl by itself or as part of arylalkyl is optionally substituted with oxo ##STR26## ##STR27## PA1 are the same or different and are independently selected from heteroaryl containing 5- or 6-ring members; and PA1 N-oxides ##STR28## PA1 thereof; and PA1 pharmaceutically acceptable salts thereof; with the provisos that where in the first formula X is CH.sub.2, and R.sup.2, R.sup.3 and R.sup.4 are each H, then R.sup.1 will be other than 3,3-diphenylpropyl, and in the fifth formula, where one of R.sup.2, R.sup.3 and R.sup.4 is 6-fluoro, and the others are H, R.sup.7 will be other than 4-(2-methoxyphenyl). PA1 X.sup.1 and X.sup.2 are independently selected from H or halo; PA1 x is an integer from 2 to 6; PA1 R.sup.5 is heteroaryl, aryl, heterocycloalkyl or cycloalkyl, each R.sup.5 group being optionally substituted with 1, 2, 3 or 4 substituents which may be the same or different. PA1 wherein q is 0, 1 or 2; PA1 A is PA1 where R.sup.5 is H or lower alkyl or R.sup.5 together with R.sup.2 forms a carbocyclic or heterocyclic ring system containing 4 to 8 members in the ring. PA1 B is a fluorenyl-type group of the structure: ##STR34## PA1 B is an indenyl-type group of the structure ##STR35## PA1 R.sup.x is H, alkyl or aryl; PA1 R.sup.1 is alkyl, alkenyl, alkynyl, alkoxyl, (alkyl or aryl).sub.3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, --PO(R.sup.13) (R.sup.14), (where R.sup.13 and R.sup.14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy); R.sup.1 can also be aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or aryloxy).sub.2 alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L.sup.1 (or L.sup.2 in the case of R.sup.2) at the 2-position); 1,3-dioxane or 1,3-dioxolane connected to L.sup.1 (or L.sup.2 in the case of R.sup.2) at the 4-position. PA1 Y is O, N--R.sup.6 or S; PA1 n' is 0, 1 or 2; PA1 R.sup.6 is H, lower alkyl, aryl, --C(O)--R.sup.11 or --C(O)--O--R.sup.11 ; PA1 R.sup.7 and R.sup.8 are the same or different and are independently H, alkyl, aryl, halogen, --O--R.sup.12, or PA1 R.sup.7 and R.sup.8 together can be oxygen to form a ketone; PA1 R.sup.9, R.sup.10, R.sup.9 ' and R.sup.10 ' are the same or different and are independently H, lower alkyl, aryl or --O--R.sup.11 ; PA1 R.sup.9 " and R.sup.10 " are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R.sup.11 ; PA1 R.sup.11 is alky or aryl; PA1 R.sup.12 is H, alkyl or aryl. PA1 (a) when R.sup.1 is unsubstituted alkyl or unsubstituted arylalkyl, L.sup.1 cannot contain amino; PA1 (b) when R.sup.1 is alkyl, L.sup.1 cannot contain amino and oxo in adjacent positions (to form an amido group); PA1 (c) when R.sup.2 L.sup.2 A-- is H.sub.2 N--, R.sup.1 L.sup.1 cannot contain amino; PA1 (d) when R.sup.1 is cyano, L.sup.1 must have more than 2 carbons; PA1 (e) R.sup.1 L.sup.1 must contain at least 3 carbons. PA1 where Z is N or CH, or where Z is ##STR40## PA1 or CH.sub.2 when {character pullout} is a single bond; PA1 Q is PA1 where R.sup.5 and R.sup.5a are the same or different and are H, lower alkyl, aryl, heteroaryl or cycloalkyl; PA1 R is H, alkyl, alkoxy, alkenyl, alkynyl, aryl, halo, heteroaryl, cycloheteroalkyl, heteroarylalkyl, cycloalkyl or cycloalkenyl, with the proviso that R cannot be alkoxy or halo when {character pullout} is a single bond; PA1 B is a fluorenyl-type group of the structure: ##STR42## PA1 B is an indenyl-type group of the structure ##STR43## PA1 R.sup.1 is alkyl, alkenyl, alkynyl, alkoxy, (alkyl or aryl).sub.3 Si (where each alkyl or aryl group is independent), cycloalkyl, cycloalkenyl, substituted alkylamino, substituted arylalkylamino, aryl, arylalkyl, arylamino, aryloxy, hydroxy, amino, heteroaryl, heteroarylamino, heteroaryloxy, arylsulfonylamino, heteroarylsulfonylamino, arylthio, arylsulfinyl, arylsulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, cycloheteroalkyl, cycloheteroalkylalkyl, --PO(R.sup.13) (R1.sup.4), (where R.sup.13 and R.sup.14 are independently alkyl, aryl, alkoxy, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, cycloheteroalkoxy, or cycloheteroalkylalkoxy); R.sup.1 can also be carbonylamino or aminocarbonyl (where the amino may optionally be substituted with one or two aryl, alkyl or heteroaryl groups); cyano, 1,1-(alkoxyl or aryloxy).sub.2 alkyl (where the two aryl or alkyl substituents can be independently defined, or linked to one another to form a ring, such as 1,3-dioxane or 1,3-dioxolane, connected to L.sup.1 at the 2, 4, 5, or 6 position). PA1 where J is: CHR.sup.23, ##STR45## PA1 R.sup.23, R.sup.24 and R.sup.25 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl; PA1 R.sup.20, R.sup.21, R.sup.22 are independently hydrogen, halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, hydroxy or haloalkyl; and these preferred substituents may either be directly attached to R.sup.1, or attached via an alkylene chain at an open position. PA1 L.sup.1 is a linking group containing from 1 to 10 carbons in a linear chain (including alkylene, alkenylene or alkynylene), which may contain, within the linking chain any of the following: one or two alkenes, one or two alkynes, an oxygen, an amino group optionally substituted with alkyl or aryl, an oxo group; and may be substituted with one to five alkyl or halo groups (preferably F). PA1 Y is O, N--R.sup.6 or S; PA1 n is 0, 1 or 2; PA1 R.sup.6 is H, lower alkyl, aryl, --C(O)--R.sup.11 or --C(O)--O--R.sup.11 ; PA1 R.sup.7 and R.sup.8 are the same or different and are independently H, alkyl, aryl, halogen, --O--R.sup.12, or PA1 R.sup.7 and R.sup.8 together can be oxygen to form a ketone; PA1 R.sup.9, R.sup.10, R.sup.9 ' and R.sup.10 ' are the same or different and are independently H, lower alkyl, aryl or --O--R.sup.11 ; PA1 R.sup.9 " and R.sup.10 " are the same or different and are independently H, lower alkyl, aryl, halogen or --O--R.sup.11 ; PA1 R.sup.11 is alky or aryl; PA1 R.sup.12 is H, alkyl or aryl. PA1 wherein u is selected f rom O, S, and NR.sup.7a ; PA1 R.sup.7a is H, lower alkyl, aryl, --C(O)R.sup.7b, --C(O) OR.sup.7b ; R.sup.7b is alkyl or aryl. PA1 X is a bond, oxygen or sulfur; PA1 R.sup.3 and R.sup.4 are the same or different and are H or F; PA1 R.sup.1 is aryl, phenyl, heteroaryl, imidazolyl, cycloheteroalkyl, pyridyl, cyclohexyl, PO(R.sup.13) (R.sup.14), heteroarylthio, benzthiazole-2-thio, benzimidazolyl, indolyl, imidazole-2-thio, alkyl, alkenyl or 1,3-dioxan-2-yl, wherein each of the above is optionally substituted; PA1 L.sup.1 is a chain containing 1 to 5 atoms in a linear chain; and A is ##STR77## PA1 where Q is S or N-alkyl and R is H or alkyl. PA1 where Z is CH; PA1 Q is ##STR79## PA1 or S where R.sup.5 is alkyl such as methyl or ethyl; PA1 {character pullout} is a double bond; PA1 R is H or alkyl such as methyl; PA1 L.sup.1 is alkylene of 2-5 carbons in the chain; and PA1 R.sup.1 is ##STR80## PA1 (1) bovine liver microsomes, PA1 (2) HepG.sub.2 cells (human hepatoma cells) or PA1 (3) recombinant human MTP expressed in baculovirus.
In the formula I compounds, where X is CH.sub.2 and R.sup.2 R.sup.3 and R.sup.4 are each H, R.sup.1 will be other than 3,3-diphenylpropyl.
In the formula III compounds, where one of R.sup.2, R.sup.3 and R.sup.4 is 6-fluoro, and the others are H, R.sup.7 will be other than 4-O-methoxyphenyl.
U.S. application Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e) discloses compounds of the structure ##STR16##
(1) when R.sup.12 is H, aryloxy, alkoxy or arylalkoxy, then Z.sup.2 is ##STR23## PA2 or a bond and PA2 (2) when Z.sup.2 is a bond, R.sup.12 cannot be heteroaryl or heteroarylalkyl; PA2 (1) a bond; PA2 (2) --O--; or ##STR33## PA2 (1) --O--; PA2 (2) --S--; or ##STR41##
U.S. application Ser. No. 548,811, filed Jan. 11, 1996 (file DC21h), discloses compounds having the structure ##STR29##
including the piperidine N-oxide thereof or a pharmaceutically acceptable salt thereof, wherein Z is a bond, O or S;
U.S. Provisional Application No. 60/017,253, filed May 10, 1996 (file HX82*) discloses compounds which are inhibitors of MTP and have the structure ##STR30##
where W is H, H or O; and X, Q, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are essentially as defined in U.S. application Ser. No. 472,067 (file DC21e).
U.S. Provisional Application No. 60/017,254, filed May 10, 1996 (file HX84*) discloses compounds which are inhibitors of MTP and have the structure ##STR31##
where n is 0 or 1 and X, Q, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are essentially as defined in U.S. application Ser. No. 472,067 (file DC21e).
U.S. Provisional Application No. 60/017,224 (file HX79a*) filed May 7, 1996, discloses compounds which are inhibitors of MTP and have the structure ##STR32##
including pharmaceutically acceptable salts thereof,
The R.sup.1 group may have from one to four substituents, which can be any of the R.sup.3 groups or R.sup.1 groups, and certain preferred R.sup.1 substituents as disclosed.
R.sup.2 is the same or different from R.sup.1 and is independently any of the groups set out for R.sup.1, H, polyhaloalkyl (such as CF.sub.3 CH.sub.2, CF.sub.3 CF.sub.2 CH.sub.2 or CF.sub.3) or cycloheteroalkyl, and may be substituted with one to four of any of the groups defined for R.sup.3, or any of the substituents preferred for R.sup.1.
L.sup.1 is a linking group containing from 1 to 10 carbons in a linear chain (including alkylene, alkenylene or alkynylene), which may contain, within the linking chain any of the following: one or two alkenes, one or two alkynes, an oxygen, an amino group optionally substituted with alkyl or aryl, an oxo group; and may be substituted with one to five alkyl or halo groups (preferably F).
L.sup.2 may be the same or different from L.sup.1 and may independently be any of the L.sup.1 groups set out above or a singe bond.
R.sup.3, R.sup.3 ', R.sup.4 and R.sup.4 ' may be the same or different and are independently selected from H, halogen, CF.sub.3, haloalkyl, hydroxy, alkoxy, alkyl, aryl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, alkanoyl, nitro, amino, thiol, alkylthio, alkylsulfinyl, alkylsulfonyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, cycloheteroalkyl, cycloheteroalkylalkyl, cyano, Ar, Ar-alkyl, ArO, Ar-amino, Ar-thio, Ar-sulfinyl, Ar-sulfonyl, Ar-carbonyl, Ar-carbonyloxy or Ar-carbonylamino, wherein Ar is aryl or heteroaryl and Ar may optionally include 1, 2 or 3 additional rings fused to Ar;
R.sup.3a and R.sup.3b are the same or different and are independently any of the R.sup.3 groups except hydroxy, nitro, amino or thio; ##STR36##
are the same or different and independently represent a 5 or 6 membered heteroaryl ring which may contain 1, 2, 3 or 4 heteroatoms in the ring which are independently N, S or O; and including N-oxides.
X (in the fluorenyl type ring) is a bond, or is one of the following groups: ##STR37##
wherein
The following provisos apply to formula I compounds:
With respect to compounds of the invention IA and IB, R.sup.2 L.sup.2 cannot have an O or N atom directly attached to S.dbd.(O).sub.q or CRX(OH), and for IA, R.sup.2 L.sup.2 cannot be H.
With respect to compounds of the invention I, IA and IB, where R.sup.1 is cycloheteroalkyl, R.sup.1 is exclusive of 1-piperidinyl, 1-pyrrolidinyl, 1-azetidinyl or 1-(2-oxo-pyrrolidinyl).